AbstractAnthropogenic disturbance may increase the emergence of zoonoses. Especially generalists that cope with disturbance and live in close contact with humans and livestock may become reservoirs of zoonotic pathogens. Yet, whether anthropogenic disturbance modifies host-pathogen co-evolutionary relationships in generalists is unknown. We assessed pathogen diversity, neutral genome-wide diversity (SNPs) and adaptive MHC class II diversity in a rodent generalist inhabiting three lowland rainforest landscapes with varying anthropogenic disturbance, and determined which MHC alleles co-occurred more frequently with 13 gastrointestinal nematodes, blood trypanosomes, and four viruses. Pathogen-specific selection pressures varied between landscapes. Genome-wide diversity declined with the degree of disturbance, while MHC diversity was only reduced in the most disturbed landscape. Furthermore, pristine forest landscapes had more functional important MHC–pathogen associations when compared to disturbed forests. We show co-evolutionary links between host and pathogens impoverished in human-disturbed landscapes. This underscores that parasite-mediated selection might change even in generalist species following human disturbance which in turn may facilitate host switching and the emergence of zoonoses.